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NCI/PDQ^® Health professionals: Pain (PDQ®)

National Cancer Institute
Last Modified: July 20, 2012

TABLE OF CONTENTS

• Overview
  • Highlights of Patient Management
  • Current Clinical Trials

• Pain Assessment
  • Initial Assessment
  • Patient Self-report
  • Physical Examination
  • Assessment of the Outcomes of Pain Management

• Pharmacologic Management
  • Basic Principles of Cancer Pain Management
  • Acetaminophen and Nonsteroidal Anti-inflammatory Drugs
  • Opioids
    • Opioid types
    • Principles of opioid administration
    • Route of administration
    • Drugs and routes to be avoided
    • Side effects of opioids
      • Constipation
      • Nausea and vomiting
      • Cognitive and other neurotoxic side effects of opioids
        • Managing cognitive and other neurotoxic effects of opioids
      • Respiratory depression
      • Subacute overdose
      • Effects of opioids on sexual function
      • Other opioid side effects
  • Adjuvant Drugs
  • Current Clinical Trials

• Palliative Interventions
  • Radiation Therapy
    • External-beam radiation for bone metastases
    • Radiopharmaceuticals
    • Radiofrequency ablation
  • Invasive Palliative Interventions
    • Nerve blocks
    • Neurologic interventions
    • Management of procedural pain

• Physical, Integrative, Cognitive-Behavioral, and Psychosocial Interventions
  • Physical Modalities
  • Integrative Modalities
  • Cognitive-Behavioral Interventions

• Discharge Planning

• Treating Elderly Patients

• Changes to This Summary (07/20/2012)

• Questions or Comments About This Summary

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

Overview

Back Up

The International Association for the Study of Pain defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Cancer pain can be managed effectively through relatively simple means in up to 90% of the eight million Americans who have cancer or a history of cancer. Unfortunately, pain associated with cancer is frequently undertreated. 1

Although cancer pain or associated symptoms often cannot be entirely eliminated, appropriate use of available therapies can effectively relieve pain in most patients. Pain management improves the patient's quality of life throughout all stages of the disease. Patients with advanced cancer experience multiple concurrent symptoms with pain; therefore, optimal pain management necessitates a systematic symptom assessment and appropriate management for optimal quality of life. 2 Despite the wide range of available pain management therapies, data are insufficient to guide their use in children, adolescents, older adults, and special populations. 3

State and local laws often restrict the medical use of opioids to relieve cancer pain, and third-party payers may not reimburse for noninvasive pain-control treatments. Thus, clinicians should work with regulators, state cancer pain initiatives, or other groups to eliminate these health care system barriers to effective pain management. (These and other barriers to effective pain management are listed below.) Changes in health care delivery may create additional disincentives for clinicians to practice effective pain management.

The U.S. Food and Drug Administration Amendments Act of 2007 requires manufacturers to provide risk evaluation and mitigation strategies (REMS) for selected drugs to ensure that benefits outweigh risks. A major component of REMS requires prescribers to obtain training so that these drugs can be safely used.

Barriers to Effective Pain Management
• Problems related to health care professionals:
  • Inadequate knowledge of pain management.
  • Poor assessment of pain. 4 5 6
  • Concern about regulation of controlled substances.
  • Fear of patient addiction. 5
  • Concern about side effects of analgesics. 4
  • Concern about patients becoming tolerant to analgesics.

• Problems related to patients:
  • Reluctance to report pain.
  • Concern about distracting physicians from treatment of underlying disease.
  • Fear that pain means disease is worse.
  • Concern about not being a good patient.
  • Reluctance to take pain medications.
  • Fear of addiction or of being thought of as an addict. (This fear may be more pronounced in minority patients.) 7
  • Worries about unmanageable side effects (such as constipation, nausea, or clouding of thought).
  • Concern about becoming tolerant to pain medications.
  • Poor adherence to the prescribed analgesic regimen. 8
  • Financial barriers. 5

• Problems related to the health care system:
  • Low priority given to cancer pain treatment. 4
  • Inadequate reimbursement for pain assessment and treatment.
  • The most appropriate treatment may not be reimbursed or may be too costly for patients and families. 5
  • Restrictive regulation of controlled substances.
  • Problems of availability of treatment or access to it.
  • Opioids unavailable in the patient's pharmacy.
  • Unaffordable medication.

Flexibility is the key to managing cancer pain. As patients vary in diagnosis, stage of disease, responses to pain and interventions, and personal preferences, so must pain management. The recommended clinical approach outlined below emphasizes a focus on patient involvement.

1. Ask about pain regularly. Assess pain and associated symptoms systematically using brief assessment tools. Assessment should include discussion about common symptoms experienced by cancer patients and how each symptom will be treated. 2 3 Asking a patient to identify his or her most troublesome symptom is also of clinical value because the most troublesome symptom is not always the most severe, as demonstrated in a survey of 146 patients in the palliative phase of treatment for lung, gastrointestinal, or breast cancer. 9
2. Believe patient and family reports of pain and what relieves the pain. (Caveats include patients with significant psychological/existential distress and patients with cognitive impairment.) 10 11
3. Choose pain-control options appropriate for the patient, family, and setting.
4. Deliver interventions in a timely, logical, coordinated fashion.
5. Empower patients and their families. Enable patients to control their course as much as possible.

Highlights of Patient Management

Effective pain management is best achieved by a team approach involving patients, their families, and health care providers. The clinician should:

• Initiate prophylactic anticonstipation measures in all patients (except those with diarrhea) before or during opiate administration. (Refer to the Constipation section in the Side Effects of Opioids section of this summary for more information.)
• Discuss pain and its management with patients and their families.
• Encourage patients to be active participants in their care.
• Reassure patients who are reluctant to report pain that there are many safe and effective ways to relieve pain.
• Consider the cost of proposed drugs and technologies.
• Share documented pain assessment and management with other clinicians treating the patient.
• Know state/local regulations for controlled substances.

In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.

Current Clinical Trials

Check NCI's list of cancer clinical trials for U.S. supportive and palliative care trials about pain that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Weiss SC, Emanuel LL, Fairclough DL, et al.: Understanding the experience of pain in terminally ill patients. Lancet 357 (9265): 1311-5, 2001. [PUBMED Abstract]
2. Meuser T, Pietruck C, Radbruch L, et al.: Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain 93 (3): 247-57, 2001. [PUBMED Abstract]
3. Patrick DL, Ferketich SL, Frame PS, et al.: National Institutes of Health State-of-the-Science Conference Statement: Symptom Management in Cancer: Pain, Depression, and Fatigue, July 15-17, 2002. J Natl Cancer Inst 95 (15): 1110-7, 2003. [PUBMED Abstract]
4. Breivik H, Cherny N, Collett B, et al.: Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes. Ann Oncol 20 (8): 1420-33, 2009. [PUBMED Abstract]
5. Sun V, Borneman T, Piper B, et al.: Barriers to pain assessment and management in cancer survivorship. J Cancer Surviv 2 (1): 65-71, 2008. [PUBMED Abstract]
6. Bruera E, Willey JS, Ewert-Flannagan PA, et al.: Pain intensity assessment by bedside nurses and palliative care consultants: a retrospective study. Support Care Cancer 13 (4): 228-31, 2005. [PUBMED Abstract]
7. Anderson KO, Richman SP, Hurley J, et al.: Cancer pain management among underserved minority outpatients: perceived needs and barriers to optimal control. Cancer 94 (8): 2295-304, 2002. [PUBMED Abstract]
8. Miaskowski C, Dodd MJ, West C, et al.: Lack of adherence with the analgesic regimen: a significant barrier to effective cancer pain management. J Clin Oncol 19 (23): 4275-9, 2001. [PUBMED Abstract]
9. Hoekstra J, Vernooij-Dassen MJ, de Vos R, et al.: The added value of assessing the 'most troublesome' symptom among patients with cancer in the palliative phase. Patient Educ Couns 65 (2): 223-9, 2007. [PUBMED Abstract]
10. Allen RS, Haley WE, Small BJ, et al.: Pain reports by older hospice cancer patients and family caregivers: the role of cognitive functioning. Gerontologist 42 (4): 507-14, 2002. [PUBMED Abstract]
11. Bruera E, Sweeney C, Willey J, et al.: Perception of discomfort by relatives and nurses in unresponsive terminally ill patients with cancer: a prospective study. J Pain Symptom Manage 26 (3): 818-26, 2003. [PUBMED Abstract]

Pain Assessment

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Failure to assess pain is a critical factor leading to undertreatment. Assessment involves both the clinician and the patient. Assessment should occur at the following times:

• At each clinical encounter.
• At regular intervals after initiation of treatment.
• At each new report of pain.
• At a suitable interval after pharmacologic or nonpharmacologic intervention (e.g., 1530 minutes after parenteral drug therapy and 1 hour after oral administration).

Identifying the etiology of pain is important to its management. Clinicians treating patients with cancer should recognize the common cancer pain syndromes (see lists below). Prompt diagnosis and treatment of these syndromes can reduce morbidity associated with unrelieved pain. Distinct cultural components may need to be incorporated into a multidimensional assessment of pain. 1 2 3 4 Reviews of cancer pain with a focus on neuropathic pain describes pathophysiologies as well as available and investigational pharmacotherapies. 5 6[Level of evidence: II]

Common Pain Syndromes: Pain Associated with Tumor
• Bone lesions/metastases
  • Bone marrow expansion
  • Vertebral syndrome
  • Local infiltration
  • Base of skull involvement

• Visceral
  • Hepatic capsule distension
  • Retroperitoneal syndrome
  • Intestinal obstruction
  • Ureteral obstruction

• Neuropathies/plexopathies
  • Cranial neuropathies
    • Leptomeningeal disease
    • Base of skull metastases

  • Mononeuropathies
  • Polyneuropathies
    • Brachial, cervical, sacral

  • Cauda equina syndrome

• Paraneoplastic syndrome
  • Osteoarthropathy
  • Gynecomastia
  • Sensorimotor neuropathy

Common Pain Syndromes: Pain Secondary to Treatment
• Postradiation therapy
  • Enteritis
  • Radiation fibrosis
  • Osteoradionecrosis
  • Myelopathy
  • Neuropathy/plexopathies
    • Brachial, sacral

  • Pain flare after radiopharmaceutical
  • Radiation-induced cystitis

• Postchemotherapy
  • Arthralgia, myalgia
    • Aromatase inhibitors

  • Avascular necrosis
  • Chronic abdominal pain
  • Mucositis
  • Neuropathy
    • Platinum-based products: Cisplatin, carboplatin, oxaliplatin
    • Taxanes: Paclitaxel, docetaxel
    • Vinca alkaloids: Vincristine, vinblastine
    • Epothilones: Ixabepilone
    • Others: Bortezomib, lenalidomide, thalidomide

• Posthormonal therapy
  • Bone pain flare
  • Arthralgia, myalgia

• Postsurgery
  • Acute postoperative or procedural pain
  • Phantom limb pain/postamputation pain
  • Postnephrectomy syndrome
  • Postmastectomy syndrome
  • Postthoracotomy syndrome
  • Postradical neck dissection
  • Pelvic floor myalgia

• Bisphosphonates
  • Bone pain, osteonecrosis

Initial Assessment

The goal of the initial assessment of pain is to characterize the pathophysiology of the pain and to determine the intensity of the pain and its impact on the patient's ability to function. For example, one study evaluated the association between psychological distress and pain in 120 patients with advanced cancer. Pain intensity and pain that interfered with walking ability, normal work, and relations with other people, as measured by the Brief Pain Inventory (Greek version), were found to be significant predictors of anxiety, as measured by the Hospital Anxiety and Depression Scale on multivariate analysis. Using the same tools, the authors also found pain that interfered with enjoyment of life was a predictor of depression. 7[Level of evidence: II] Factors that may influence analgesic response and result in persistent pain include changing nociception due to disease progression, intractable side effects, tolerance, neuropathic pain, and opioid metabolites. 8[Level of evidence: IV] The following are essential to the initial assessment:

• Detailed medical and pain history.
• Physical examination.
• Psychosocial and spiritual assessment. 9[Level of evidence: IV]
• History of substance abuse in patient and family.
• Diagnostic evaluation.

The experience of cancer pain is complex and includes physical, psychosocial, and spiritual dimensions. There is no universally accepted pain classification measure that assists with predicting the complexity of pain management, particularly for cancer pain patients, who may be more difficult to treat. Clinicians and researchers lack a common language to discuss and compare outcomes of cancer pain assessment and management. Oncologists use the tumor, nodes, metastases (TNM) system as a universal language to describe a variety of cancers. The need for a similar classification system for cancer pain resulted in the development of the Edmonton Staging System. 10 11 This system has been further refined in two reports that have gathered construct validity evidence using an international panel of content experts 12 and a multicenter study to determine interrater reliability and predictive value. 13 The development of an internationally recognized classification system for cancer pain could play a significant role in improving the assessment of cancer pain, allow a more meaningful assessment of clinical prognosis and treatment, and better enable researchers to compare results with regard to cancer pain management. 14[Level of evidence: II]

Patient Self-report

The mainstay of pain assessment is the patient self-report; however, family caregivers are often used as proxies for patient reports, especially in situations in which communication barriers exist, such as cognitive impairment or language difficulties. Family members who act as proxies typically, as a group, report higher levels of pain than patient self-reports, but there is individual variation. 15 16[Level of evidence: II] Differences in clinician assessment of pain intensity are also significant. A retrospective review of 41 patient charts using pain ratings of palliative care consultants as the gold standard found high agreement with assessments performed by bedside nurses (registered nurses [RNs] and clinical nurse assistants [CNAs]) when pain was not present or was mild but poor agreement for moderate or severe pain (sensitivity: RNs, 45%; CNAs, 30%). 17[Level of evidence: III]

Pain assessment tools may be unidimensional or multidimensional. Multiple assessment tools exist. Among the more commonly used bedside tools are numeric rating scales, verbal rating scales, visual analog scales, and picture scales. 18 19[Level of evidence: IV] Pain intensity at initial assessment has been demonstrated to be a significant predictor of subsequent pain management complexity (i.e., the need for more pharmacological and multidimensional approaches) and length of time to achieve stable pain control. 20[Level of evidence: II] To enhance pain management across all settings, clinicians should teach families to use pain assessment tools in their homes. The clinician should help the patient to describe:

Pain
• Listen to the patient's descriptive words about the quality of the pain; these provide valuable clues to its etiology. Elicit the temporal features including onset, duration, and diurnal variation. Ask about breakthrough or episodic pain (a transitory increase in pain that occurs in addition to persistent pain). Some patients may have episodic pain without persistent pain. 21[Level of evidence: IV]

Location
• Ask the patient to indicate the exact location of the pain on his or her body, or on a body diagram, and whether the pain radiates.

Changes in Pattern
• Changes in pain pattern or the development of new pain should trigger diagnostic reevaluation and modification of the treatment plan. Persistent pain indicates the need to consider other etiologies (e.g., related to disease progression or treatment) and alternative (perhaps more invasive) treatments.

Intensity or Severity
• Encourage the patient to keep a log of pain-intensity scores to report during follow-up visits or by telephone. Examples of simple self-report pain-intensity scales include the simple, descriptive, numeric, and visual analog scales.

Aggravating and Relieving Factors
• Ask the patient to identify factors that cause the most pain and also what relieves the pain.

Cognitive Response to Pain
• Cognitive appraisals of pain can be based on a range of psychological variables such as perceived control, meaning attributed to pain experience, fear of death, and hopelessness. 22 All these variables appear to contribute to the experience of cancer pain and suffering. A study of women with metastatic breast cancer found that although the site of metastasis did not predict the intensity of pain report, greater depression and the belief that pain represented the spread of disease significantly predicted the degree of pain experienced. 23 It was also reported that patients who thought that their pain represented disease progression reported more pain-related interference with function. 24[Level of evidence: II]

Cognitive Impairment
• Note behavior that suggests pain in patients who are cognitively impaired or who have communication problems relating to education, language, ethnicity, or culture. Cognitive impairment itself and the degree of cognitive impairment may impact patient self-report of pain. Preliminary data suggest that mild degrees of cognitive impairment are associated with increased intensity of pain-report in older patients with cancer who are receiving hospice care. 15 In contrast, cognitively impaired nursing home residents are less likely to report pain. Use appropriate (e.g., simpler or translated) pain assessment tools.

Goals for Pain Control
• Document the patient's preferred pain assessment tool and the goals for pain control (such as scores on a pain scale).
• Encourage use of the pain diary: The daily pain diary is a well-established tool in symptom management research and in clinical practice. Benefits of using a pain diary include heightened awareness of pain, guidance for pain management behaviors, enhanced sense of control, and a tool for communication. 25 It is difficult to get good pain-diary compliance with adolescents who are experiencing intense chronic pain.

Physical Examination

A thorough physical examination is required to determine the pathophysiology of pain. Specific features of the neurologic examination such as altered sensation (hypoesthesia, hyperesthesia, hyperpathia, allodynia) in a painful area are suggestive of neuropathic pain. Physical findings of tumor growth and metastasis are also important to identify.

Information obtained from the synthesis of history, physical examination, and diagnostic evaluations is used to generate a pain diagnosis with respect to etiology (cancer, its treatment, or other) and pathophysiology (somatic, visceral, and/or neuropathic). This diagnosis, in conjunction with contributing psychosocial and spiritual factors, is used to generate a comprehensive pain treatment plan.

Assessment of the Outcomes of Pain Management

Pain-related outcomes: Clinicians should document and be aware of outcomes of pain therapy. It is helpful to think of pain-related outcomes as primarily measured in two ways: decreased pain intensity and improvement in psychosocial functioning. Using rating scales of pain intensity at its worst and on average and using pain interference scales can help clinicians monitor outcomes. Measurement of the percentage of pain relief is also useful, though measuring patient satisfaction is less useful because of the low expectations patients sometimes hold for pain control. 26 27

Drug-taking outcomes: Clinicians prescribing chronic opioids should also monitor and document patients' drug-taking behaviors. Outcomes related to addiction in cancer patients are rare but nonetheless should be periodically assessed; these assessments can be reassuring to patients. Tolerance and dependence are not addiction related. Documentation of patients' compliance with regard to changes in dosing and duration of prescriptions is essential in all pain practice.

The clinical assessment of drug-taking behaviors in medically ill patients with pain is complex. Aberrant drug-taking behavior from cancer pain management is related to premorbid history of drug addiction and the likelihood of other pain treatment. A pilot questionnaire was used to characterize drug-related behaviors and attitudes in cancer and AIDS patients. Despite limitations, this study highlights wide potential variation among different palliative care populations in patterns of past and present aberrant drug-taking behaviors and the need for a clinically useful screening approach. The implications for psychosocial and pharmacological management of symptoms such as pain, as well as any aberrant behavior, remain unclear. 28 29 30

Previous drug abuse is likely to lead to specific needs for appropriate dosing during cancer pain therapy. A prospective open-label study compared morphine dosage and effectiveness in AIDS patients with and without previous substance abuse. Results demonstrated that both groups benefited, but patients with a history of drug use required and tolerated substantially higher morphine doses to achieve stable pain control. 31[Level of evidence: II] This study should increase confidence in providing appropriate pain management to patients who have a history of drug use. 32[Level of evidence: IV]

References:

1. Chung JW, Wong TK, Yang JC: The lens model: assessment of cancer pain in a Chinese context. Cancer Nurs 23 (6): 454-61, 2000. [PUBMED Abstract]
2. Cleeland CS, Nakamura Y, Mendoza TR, et al.: Dimensions of the impact of cancer pain in a four country sample: new information from multidimensional scaling. Pain 67 (2-3): 267-73, 1996. [PUBMED Abstract]
3. Greenwald HP: Interethnic differences in pain perception. Pain 44 (2): 157-63, 1991. [PUBMED Abstract]
4. Bates MS, Edwards WT, Anderson KO: Ethnocultural influences on variation in chronic pain perception. Pain 52 (1): 101-12, 1993. [PUBMED Abstract]
5. Fine PG, Miaskowski C, Paice JA: Meeting the challenges in cancer pain management. J Support Oncol 2 (6 Suppl 4): 5-22; quiz 23-4, 2004 Nov-Dec. [PUBMED Abstract]
6. Maías A, Monroy JL, Ramos AA, et al.: Prevalence of neuropathic pain in radiotherapy oncology units. Int J Radiat Oncol Biol Phys 81 (2): 511-20, 2011. [PUBMED Abstract]
7. Mystakidou K, Tsilika E, Parpa E, et al.: Psychological distress of patients with advanced cancer: influence and contribution of pain severity and pain interference. Cancer Nurs 29 (5): 400-5, 2006 Sep-Oct. [PUBMED Abstract]
8. Mercadante S, Portenoy RK: Opioid poorly-responsive cancer pain. Part 1: clinical considerations. J Pain Symptom Manage 21 (2): 144-50, 2001. [PUBMED Abstract]
9. Otis-Green S, Sherman R, Perez M, et al.: An integrated psychosocial-spiritual model for cancer pain management. Cancer Pract 10 (Suppl 1): S58-65, 2002 May-Jun. [PUBMED Abstract]
10. Bruera E, MacMillan K, Hanson J, et al.: The Edmonton staging system for cancer pain: preliminary report. Pain 37 (2): 203-9, 1989. [PUBMED Abstract]
11. Bruera E, Schoeller T, Wenk R, et al.: A prospective multicenter assessment of the Edmonton staging system for cancer pain. J Pain Symptom Manage 10 (5): 348-55, 1995. [PUBMED Abstract]
12. Nekolaichuk CL, Fainsinger RL, Lawlor PG: A validation study of a pain classification system for advanced cancer patients using content experts: the Edmonton Classification System for Cancer Pain. Palliat Med 19 (6): 466-76, 2005. [PUBMED Abstract]
13. Fainsinger RL, Nekolaichuk CL, Lawlor PG, et al.: A multicenter study of the revised Edmonton Staging System for classifying cancer pain in advanced cancer patients. J Pain Symptom Manage 29 (3): 224-37, 2005. [PUBMED Abstract]
14. Fainsinger RL, Nekolaichuk CL: A "TNM" classification system for cancer pain: the Edmonton Classification System for Cancer Pain (ECS-CP). Support Care Cancer 16 (6): 547-55, 2008. [PUBMED Abstract]
15. Allen RS, Haley WE, Small BJ, et al.: Pain reports by older hospice cancer patients and family caregivers: the role of cognitive functioning. Gerontologist 42 (4): 507-14, 2002. [PUBMED Abstract]
16. Black B, Herr K, Fine P, et al.: The relationships among pain, nonpain symptoms, and quality of life measures in older adults with cancer receiving hospice care. Pain Med 12 (6): 880-9, 2011. [PUBMED Abstract]
17. Bruera E, Willey JS, Ewert-Flannagan PA, et al.: Pain intensity assessment by bedside nurses and palliative care consultants: a retrospective study. Support Care Cancer 13 (4): 228-31, 2005. [PUBMED Abstract]
18. Jensen MP, Karoly P: Measurement of cancer pain via patient self-report. In: Chapman CR, Foley KM, eds.: Current and Emerging Issues in Cancer Pain: Research and Practice. New York, NY: Raven Press, 1993, pp 193-218. [PUBMED Abstract]
19. Hílen JC, Hjermstad MJ, Loge JH, et al.: Pain assessment tools: is the content appropriate for use in palliative care? J Pain Symptom Manage 32 (6): 567-80, 2006. [PUBMED Abstract]
20. Fainsinger RL, Fairchild A, Nekolaichuk C, et al.: Is pain intensity a predictor of the complexity of cancer pain management? J Clin Oncol 27 (4): 585-90, 2009. [PUBMED Abstract]
21. Mercadante S, Radbruch L, Caraceni A, et al.: Episodic (breakthrough) pain: consensus conference of an expert working group of the European Association for Palliative Care. Cancer 94 (3): 832-9, 2002. [PUBMED Abstract]
22. Mystakidou K, Tsilika E, Parpa E, et al.: Exploring the relationships between depression, hopelessness, cognitive status, pain, and spirituality in patients with advanced cancer. Arch Psychiatr Nurs 21 (3): 150-61, 2007. [PUBMED Abstract]
23. Spiegel D, Bloom JR: Pain in metastatic breast cancer. Cancer 52 (2): 341-5, 1983. [PUBMED Abstract]
24. Daut RL, Cleeland CS: The prevalence and severity of pain in cancer. Cancer 50 (9): 1913-8, 1982. [PUBMED Abstract]
25. Schumacher KL, Koresawa S, West C, et al.: The usefulness of a daily pain management diary for outpatients with cancer-related pain. Oncol Nurs Forum 29 (9): 1304-13, 2002. [PUBMED Abstract]
26. Rhodes DJ, Koshy RC, Waterfield WC, et al.: Feasibility of quantitative pain assessment in outpatient oncology practice. J Clin Oncol 19 (2): 501-8, 2001. [PUBMED Abstract]
27. Hwang SS, Chang VT, Kasimis B: Dynamic cancer pain management outcomes: the relationship between pain severity, pain relief, functional interference, satisfaction and global quality of life over time. J Pain Symptom Manage 23 (3): 190-200, 2002. [PUBMED Abstract]
28. Passik SD, Kirsh KL, McDonald MV, et al.: A pilot survey of aberrant drug-taking attitudes and behaviors in samples of cancer and AIDS patients. J Pain Symptom Manage 19 (4): 274-86, 2000. [PUBMED Abstract]
29. Kirsh KL, Whitcomb LA, Donaghy K, et al.: Abuse and addiction issues in medically ill patients with pain: attempts at clarification of terms and empirical study. Clin J Pain 18 (4 Suppl): S52-60, 2002 Jul-Aug. [PUBMED Abstract]
30. Passik SD, Kirsh KL, Whitcomb L, et al.: A new tool to assess and document pain outcomes in chronic pain patients receiving opioid therapy. Clin Ther 26 (4): 552-61, 2004. [PUBMED Abstract]
31. Kaplan R, Slywka J, Slagle S, et al.: A titrated morphine analgesic regimen comparing substance users and non-users with AIDS-related pain. J Pain Symptom Manage 19 (4): 265-73, 2000. [PUBMED Abstract]
32. Whitcomb LA, Kirsh KL, Passik SD: Substance abuse issues in cancer pain. Curr Pain Headache Rep 6 (3): 183-90, 2002. [PUBMED Abstract]

Pharmacologic Management

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Basic Principles of Cancer Pain Management

The World Health Organization (WHO) has described a three-step analgesic ladder as a framework for pain management. 1 It involves a stepped approach based on the severity of the pain. If the pain is mild, one may begin by prescribing a Step 1 analgesic such as acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID). Potential adverse effects should be noted, particularly the renal and gastrointestinal adverse effects of the NSAIDs. If pain persists or worsens despite appropriate dose increases, a change to a Step 2 or Step 3 analgesic is indicated. Most patients with cancer pain will require a Step 2 or Step 3 analgesic. Step 1 can be skipped in those patients presenting at the onset with moderate-to-severe pain in favor of Step 2 or Step 3. At each step, an adjuvant drug or modality such as radiation therapy may be considered in selected patients. WHO recommendations are based on worldwide availability of drugs and not strictly on pharmacology.

Analgesics should be given by mouth, by the clock, by the ladder, and for the individual. 1 This requires regular scheduling of the analgesic, not just as needed. In addition, rescue-doses for breakthrough pain need to be added. The oral route is preferred as long as a patient is able to swallow. Each analgesic regimen should be adjusted for the patient's individual circumstances and physical condition.

Acetaminophen and Nonsteroidal Anti-inflammatory Drugs

NSAIDs are effective for relief of mild pain and may have an opioid dosesparing effect that helps reduce side effects when given with opioids for moderate-to-severe pain. Acetaminophen is included with aspirin and other NSAIDs because it has similar analgesic potency, though it lacks peripheral anti-inflammatory activity. 2[Level of evidence: I] Side effects can occur at any time, and patients who take acetaminophen or NSAIDs, especially elderly patients, should be followed up carefully. 3 4 5 There is growing debate about whether NSAIDs are useful and have significant opioid-sparing effects. One meta-analysis 6 suggests that the usefulness of NSAIDs is limited and that they do not significantly spare opioid doses. Another study suggests that NSAIDs are useful and reduce the need for opioid dose increases; however, only patients with pain progression after 1 week of opioid stabilization were selected for the study. 7[Level of evidence: I]

The coxibs are a subclass of NSAIDs designed to selectively inhibit cyclooxygenase-2 (COX-2). 8 Development of these drugs was based on the hypothesis that COX-2 was the source of prostaglandins E2 and I2, which mediate inflammation, and that COX-1 was the source of the same prostaglandins in gastric epithelium, with the potential advantage of less gastrointestinal ulceration and bleeding and the absence of platelet inhibition over traditional NSAIDs. Direct comparisons between COX-2 inhibitors are few. A systematic meta-analysis of COX-2 inhibitors compared with traditional NSAIDs or different COX-2 inhibitors for postoperative pain suggests that rofecoxib, 50 mg, and parecoxib, 40 mg, are equipotent to traditional NSAIDs for postoperative pain after minor and major surgical procedures and have a longer duration of action after dental surgery. Rofecoxib was found to provide superior analgesic effect compared with celecoxib, 200 mg. There were insufficient data to comment on toxicity. 9[Level of evidence: I]

There are three coxibs that were approved by the U.S. Food and Drug Administration (FDA): celecoxib, rofecoxib, and valdecoxib. On September 30, 2004, rofecoxib was withdrawn from the market after a study demonstrated that subjects in a colon cancer prevention trial who took the drug at higher-than-typical doses on a long-term basis had a significant increase in the incidence of serious thromboembolic complications. The question that remains unanswered is whether the increased risk applies to all COX-2 inhibitors, with the caution that the burden of proof rests with those who might claim that this is a problem for rofecoxib alone and does not extend to other coxibs. 8 10 On April 7, 2005, valdecoxib was withdrawn from the market. FDA is also asking manufacturers of all marketed prescription NSAIDs, including celecoxib (Celebrex), to revise the labeling (package insert) for their products to include a boxed warning, highlighting the potential for increased risk of cardiovascular events and/or the serious, potentially life-threatening gastrointestinal bleeding associated with use of these drugs.

Dosage
• Use patient response to determine the effective dosing interval for aspirin, acetaminophen, and other NSAIDs listed in Table 1. When pain relief is not attained with the maximum dosage of one NSAID, try other drugs within this category before abandoning NSAID therapy.

Route of administration
• Use readily available oral tablets, capsules, or liquid. During intervals of nausea and vomiting, use suppositories, unless the nausea is NSAID related. Ketorolac tromethamine is the only NSAID available for parenteral use.

Contraindications
• Patients taking NSAIDs are at risk for platelet dysfunction that may impair blood clotting. Table 1 lists NSAIDs with minimal antiplatelet activity.

Other side effects
• Observe patients carefully for adverse effects, which range from mild gastrointestinal discomfort to more serious problems, including the following:
  • Gastric ulceration.
  • Hepatic dysfunction.
  • Myocardial infarction.
  • Renal failure.

  Because both NSAIDs and other drugs (e.g., warfarin, methotrexate, digoxin, cyclosporine, oral antidiabetic agents, and sulfonamide-containing drugs) are highly protein-bound, there is potential for altered efficacy or toxicity when they are given simultaneously.

Table 1. Dosing Recommendations for Acetaminophen and NSAIDs^a

^aOnly the NSAIDs listed here have FDA approval for use as simple analgesics, but clinical experience has also been gained with other drugs.^bAcetaminophen and NSAID dosages for adults weighing less than 50 kg should be adjusted for weight. ^cAcetaminophen lacks the peripheral anti-inflammatory and antiplatelet activities of the other NSAIDs. ^dThe standard against which other NSAIDs are compared. May inhibit platelet aggregation for longer than 1 week and may cause bleeding. Aspirin is not recommended for pain in children.^eMay have minimal antiplatelet activity. ^fAdministration with antacids may decrease absorption. ^gUse limited to 5 days or fewer. ^hCoombs-positive autoimmune hemolytic anemia has been associated with prolonged use. ^IHas the same gastrointestinal toxic effects as oral NSAIDs.

Drug	Usual Dose for Adults and Children 50 kg Body Weight	Usual Dose for Adults and Childrenb <50 kg Body Weight
Orally Administered Acetaminophen and Over-the-counter NSAIDs
acetaminophenc	650 mg q4h	1015 mg/kg q4h
	975 mg q6h	1520 mg/kg q4h (rectal)
aspirind	650 mg q4h	1015 mg/kg q4h
	975 mg q6h	1520 mg/kg q4h (rectal)
ibuprofen (Motrin, Advil)	400600 mg q6h	510 mg/kg q46h
magnesium salicylate (Doan's, Magan, Mobidin, others)	650 mg q4h
naproxen (Naprosyn, Aleve)	250275 mg q68h	5 mg/kg q8h
naproxen sodium (Anaprox)	275 mg q68h
Prescription NSAIDs
carprofen (Rimadyl)	100 mg tid
choline magnesium trisalicylatee (Trilisate)	1,0001,500 mg q68h	25 mg/kg q68h
choline salicylatee (Arthropan)	870 mg q34h
diclofenac (oral) (Voltaren - 1% topical; Pennsaid - 1.5% topical)	50 mg bidtid oral; 32 g/d topical	Flector (patch): 1 patch bid
diflunisalf (Dolobid)	500 mg q12h
etodolac (Lodine)	200400 mg q68h
fenoprofen calcium (Nalfon)	300600 mg q6h
ketoprofen (Orudis)	2560 mg q68h
ketorolac tromethamineg (Toradol)	10 mg q46h to a maximum of 40 mg/d
	IV administration should not exceed 5 days
meclofenamate sodiumh (Meclomen)	50100 mg q6h
mefenamic acid (Ponstel)	250 mg q6h
sodium salicylate (Anacin, Bufferin)	325650 mg q34h
Parenteral NSAIDs
acetaminophen injection	1,000 mg q6h (adults)	15 mg/kg max, 75 mg/kg in 24 h (children aged <13 y)
ketorolac tromethamineg,i (Toradol)	60 mg initially, then 30 mg q6h
	IV administration should not exceed 5 days
bid = twice a day; IV = intravenous; NSAID = nonsteroidal anti-inflammatory drug; q = every; tid = 3 times a day.

Opioids

Opioids, the major class of analgesics used in management of moderate-to-severe pain, are effective, are easily titrated, and have a favorable benefit-to-risk ratio.

The predictable consequences of long-term opioid administrationtolerance and physical dependenceare often confused with psychological dependence (addiction) that manifests as drug abuse. This misunderstanding can lead to ineffective prescribing, administering, or dispensing of opioids for cancer pain. The result is undertreatment of pain. 11

Clinicians may be reluctant to give high doses of opioids to patients with advanced disease because of a fear of respiratory depression. Many patients with cancer pain become opioid tolerant during long-term opioid therapy. Therefore, the clinician's fear of shortening life by increasing opioid doses is usually unfounded.

Opioid types

Opioids are classified as full morphine-like agonists, partial agonists, or mixed agonist-antagonists, depending on the specific receptors to which they bind and their activity at these receptors. The benefits of using opioids and the risks associated with their use vary among individuals.

Morphine is the most commonly used opioid in cancer pain management, largely for reasons of availability and familiarity; 12 however, it is useful to be familiar with more than one type of opioid. Wide interindividual variability in response to both the analgesic and adverse effects of opioids is recognized. 13 Some patients may not experience adequate pain control despite appropriate dose adjustments, while others may develop intolerable adverse effects to one particular opioid (see below). Alternative opioids include hydromorphone, oxycodone, oxymorphone, methadone, and fentanyl. Knowledge of several medications and formulations gives the caregiver much more flexibility in tailoring a regime to a particular patient's needs.

Short-acting opioids are generally recommended when opioid therapy is being initiated for the first time or when patients are medically unstable or the pain intensity is highly variable. Once stable, patients can be switched to a controlled-release or slow-release formulation. This is more convenient and promotes compliance. (Refer to Table 3 in the Principles of Opioid Administration section of this summary for more information.)

Full agonists
• Morphine, hydromorphone, codeine, oxycodone, oxymorphone, hydrocodone, methadone, levorphanol, and fentanyl are classified as full agonists because their effectiveness with increasing doses is not limited by a ceiling. Full agonists will not reverse or antagonize the effects of other full agonists given simultaneously.

Morphine
• The most commonly used opioid, morphine, is readily available in several forms, including sustained-release (824 hours duration of effectiveness) formulations for oral administration.

Other agonists
• For the patient who experiences dose-limiting side effects with one oral opioid (e.g., hallucinations, nightmares, dysphoria, nausea, or mental clouding), other oral opioids should be tried before abandoning one route in favor of another.

Methadone

• Methadone has had a revival in interest for the management of cancer pain. Published reports have been in the form of case reports, 14 15 16 17 18 19 20[[Level of evidence: IIILevel of evidence: III] outcome surveys,] outcome surveys, 21 22 23 24 25[[Level of evidence: IILevel of evidence: II][][Level of evidence: IIILevel of evidence: III] and reviews.] and reviews. 26 27 28[[Level of evidence: IVLevel of evidence: IV] Success has been reported with oral, intravenous (IV), and suppository methadone use. Subcutaneous ] Success has been reported with oral, intravenous (IV), and suppository methadone use. Subcutaneous methadone has been reported to cause tissue irritation at the injection site but has been used effectively in some patients without clinically significant local toxicity.methadone has been reported to cause tissue irritation at the injection site but has been used effectively in some patients without clinically significant local toxicity. 29[[Level of evidence: IILevel of evidence: II]]

  Methadone is a synthetic opioid agonist that has been reported to have a number of unique characteristics. These include excellent oral and rectal absorption, no known active metabolites, prolonged duration of action resulting in longer administration intervals, and lower cost than other opioids. Methadone is available as a pill, an elixir, and for parenteral use. Methadone has an average oral bioavailability of approximately 80% (range, 41%99%). 30

  Morphine is the international gold standard for first-line treatment of cancer pain. Methadone, however, can be considerably less expensive than existing rapid-release or sustained-release morphine or other opioid options. A randomized trial of 103 patients compared the effectiveness and side effects of morphine and methadone as first-line treatments for cancer pain. The outcome of successful pain management was similar for both groups; however, there were significantly more opioid-related dropouts in the methadone group. This study did not demonstrate superior analgesic effectiveness or overall tolerability of methadone over morphine as a first-line treatment for cancer pain. Despite this finding, the authors of this report suggested that study limitations did not allow definitive conclusions that methadone could not be a useful first-line opioid. Further research exploring other doses and schedules of methadone should still be explored. 31[[Level of evidence: ILevel of evidence: I]]

  Because of its long and unpredictable half-life and relatively unknown equianalgesic dose as compared with other opioids, methadone has been generally used by pain specialists with experience in its use. The utility of methadone in cancer pain and difficult cancer pain syndromes such as neuropathic pain has become more widely appreciated and has gained increasing acceptance for use in hospital and hospice settings and by clinician